Plasma lipoproteins play a critical role in the pathophysiology of atherosclerosis. Recent studies suggest that elevated high density lipoprotein (HDL) correlates negatively with the incidence of heart dsease. Further, there is evidence that longevity is statistically associated with elevated HDL and juvenile diabetes, a disease complicated by a high incidence of athlerosclerosis, is statistically assciated with decreased HDL. In this regard we have developed a hypothesis to explain the relationship of the structure of HDL to its probable function: (1) The lipid-associating properties of apo HDL are largely dependent upon the presence of well-defined polypeptide domains termed amphiatic helixes. (2) The reversibility of amphiatic helixes in their association with HDL lipids is important in controlling the surface free energy of this lipoprotein and thus its presumed tendency to act as a scavenger of cholesterol from peripheral cell membranes. We propose to test the amphipathic helix model by peptide synthesis experiments designed to determine the molecular functions of the three definable features of amphipathic helixes: length, hydrophobicity of the nonpolar face, and charge distribution of the polar face. These experiments have the advantage that factors controlling lipid affinity and structure can be delineated at the molecular level by simple amino acid sequence substitutions. In initial experiments we have synthesized an anphipathic peptide which has many of the lipid-associating properties of apo HDL.